The present invention relates to compounds that are sulfonamides, and to methods of treating atherosclerosis, coronary heart disease, and restenosis using the sulfonamide compounds. The invention also relates to a pharmaceutical composition that comprises a sulfonamide of the present invention.
Vascular diseases such as coronary heart disease, atherosclerosis, stroke, restenosis, and peripheral vascular disease, remain the leading cause of death and disability throughout the world. About 1.5 million people die each year in the United States alone from myocardial infarction resulting from congestive heart failure. While diet and life style can accelerate the onset of vascular diseases, genetic predisposition leading to dyslipidemia is a significant factor in vascular-related disabilities and deaths. xe2x80x9cDyslipidemiaxe2x80x9d means abnormal levels of lipoproteins in blood plasma.
Several risk factors have been associated with increased risk of vascular disease. Among these are the dyslipidemias of high levels of low-density lipoprotein (LDL), and low levels of high-density lipoproteins (HDL). The ratio of HDL- to LDL-cholesterol is often used to assess the risk of vascular disease. A high ratio of HDL/LDL cholesterol is desirable. Compounds that increase this ratio by either lowering LDL or increasing HDL, or both, therefore are beneficial. Recent studies have also shown that elevated levels of lipoprotein(a), xe2x80x9cLp(a)xe2x80x9d, are detrimental.
Lp(a) appears to be undesirable, since elevated levels of Lp(a) have been associated with the development of atherosclerosis, coronary heart disease, myocardial infarction, stroke, cerebral infarction, and restenosis following balloon angioplasty. In fact, Lp(a) appears to be an excellent predictor for stroke. Accordingly, a high concentration of Lp(a) is one of the major risk factors leading to death from heart disease.
Lp(a) is composed of LDL and a high molecular weight glycoprotein called apolipoprotein(a), apo(a). Epidemiological studies show that, when present in high levels in the plasma, Lp(a) is an independent risk factor for premature atherosclerotic coronary heart disease. A concentration of 0.30 g/L in plasma is considered to double the risk of premature coronary heart disease. This concentration has been used as a clinical set point to determine what plasma concentrations of Lp(a) are considered above normal and for which treatment to lower plasma Lp(a) levels may be desirable.
The present invention provides compounds of the Formula I 
wherein
R1 is heteroaryl, substituted heteroaryl, xe2x80x94(CH2)n-C3-C8 cycloalkyl, xe2x80x94(CH2)n-aryl, or xe2x80x94(CH2)n-substituted aryl;
R2 is C1-C6 alkyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, or 
n is 0 to 4, and the pharmaceutically acceptable salts thereof.
In a preferred embodiment, R3 is 
In a preferred embodiment, R2 is 
In a preferred embodiment, R1 is pyridyl, xe2x80x94CH2-cyclohexyl, 
In a more preferred embodiment, the present invention provides compounds of the Formula I 
wherein
R1 is pyridyl, xe2x80x94CH2 cyclohexyl, or -substituted pyridyl;
R2 is -thienyl-pyridyl, -C1-C6 alkyl, substituted phenyl, thienyl, or xe2x80x94CH2-phenyl;
R3 is 
xe2x80x83and the pharmaceutically acceptable salts thereof.
In a most preferred embodiment, the present invention provides the compounds:
5-Pyridin-2-yl-thiophene-2-sulfonic acid (3,5-di-tert-butyl-4-hydroxy-benzyl)-pyridin-3-yl-amide;
(Cyclohexylmethyl-methanesulfonyl-amino)-(3,5-di-tert-butyl-4-hydroxy-phenyl)-acetic acid ethyl ester;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-4-methyl-N-pyridin-3-yl-benzenesulfonamide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-4-fluoro-N-pyridin-3-yl-benzenesulfonamide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-4-nitro-N-pyridin-3-yl-benzenesulfonamide;
Thiophene-2-sulfonic acid (3,5-di-tert-butyl-4-hydroxy-benzyl)-6-methoxy-pyridin-3-yl-amide;
Thiophene-2-sulfonic acid (3,5-di-tert-butyl-4-hydroxy-benzyl)-pyridin-3-yl-amide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-4-acetamido-N-pyridin-3-yl-benzenesulfonamide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-4-methoxy-N-pyridin-3-yl benzenesulfonamide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-3-nitro-N-pyridin-3-yl-benzenesulfonamide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-3-N-pyridin-3-yl-benzenesulfonamide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-N-pyridin-3-yl-methanesulfonamide;
N-(2-Chloro-pyridin-3-yl)-N-(3,5-di-tert-butyl-4-hydroxy-benzyl)-4-methyl-benzenesulfonamide;
N-(3,5-di-tert-butyl-4-hydroxybenzyl)-2-bromo-N-pyridin-3-yl-benzenesulfonamide;
N-(6-Chloro-pyridin-3-yl)-N-(3,5-di-tert-butyl-4-hydroxybenzyl)-4-methyl-benzenesulfonamide;
N-(3,5-di-tert-butyl-4-hydroxybenzyl)-2-naphthalene-N-pyridin-3-yl-sulfonamide;
N-(3,5-di-tert-butyl-4-hydroxy-benzyl)-N-(6-methoxy-pyridin-3-yl)-4-methyl-benzenesulfonamide; and
N-(3,5-di-tert-butyl-4-hydroxybenzyl)-3-bromo-N-pyridin-3-yl-benzenesulfonamide.
Also provided is a pharmaceutical composition comprising a compound of Formula I.
Also provided is a method of lowering plasma Lp(a) in a patient, the method comprising administering to a patient in need of Lp(a) lowering a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating coronary heart disease, the method comprising administering to a patient having coronary heart disease a therapeutically effective amount of a compound of Formula 1.
Also provided is a method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound of Formula I.
The term xe2x80x9calkylxe2x80x9d means a straight or branched hydrocarbon having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl group can also be substituted with one or more of the substituents listed below for aryl.
The term xe2x80x9carylxe2x80x9d means an aromatic ring such as phenyl, 5-fluorenyl, 1-naphthyl, or 2-naphthyl group, unsubstituted or substituted by 1 to 3 substituents which can be selected from, but not limited to, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, and xe2x80x94Sxe2x80x94C1-C6 alkyl, xe2x80x94OH, xe2x80x94SH, xe2x80x94F, xe2x80x94CN, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94CO2H, xe2x80x94CO2C1-C6 alkyl, xe2x80x94NH2, xe2x80x94NHC1-C6 alkyl, N(C1-C6alkyl)2, or 
The term xe2x80x9cheteroarylxe2x80x9d means an aromatic ring containing one or more heteroatoms. Examples of heteroaryl radicals include thienyl, furyl, pyrrolyl, pyridyl, imidazolyl, or indolyl group, substituted or unsubstituted by 1 or 2 substituents from the group of substituents described above for aryl. Examples of heteroatoms include nitrogen, oxygen, sulfur, and phosphorus.
The term xe2x80x9ccycloalkylxe2x80x9d means a saturated hydrocarbon ring which contains from 3 to 7 carbon atoms, and includes for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like. The cycloalkyl group can be substituted with from 1 to 3 substituents from the group of substituents described above for aryl.
The symbol xe2x80x9cxe2x88x92xe2x80x9d means a bond.
The term xe2x80x9cpatientxe2x80x9d means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.
A xe2x80x9ctherapeutically effective amountxe2x80x9d is an amount of a compound of the present invention that when administered to a patient ameliorates a symptom of or prevents atherosclerosis, coronary heart disease, or restenosis, or lowers plasma levels of Lp(a). A therapeutically effective amount of a compound of the present invention can be easily determined by one skilled in the art by administering a quantity of a compound to a patient and observing the result. In addition, those skilled in the art are familiar with identifying patients having restenosis, coronary heart disease, or atherosclerosis or who are at risk of having restenosis, coronary heart disease, or atherosclerosis.
The term xe2x80x9cpharmaceutically acceptable salts, esters, amides, and prodrugsxe2x80x9d as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9csaltsxe2x80x9d refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, Berge S. M. et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C1-C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alkyl amines and secondary C1-C6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, xe2x80x9cPro-drugs as Novel Delivery Systems,xe2x80x9d Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference.
The compounds of the present invention can be administered to a patient alone or as part of a composition that contains other components such as excipients, diluents, and carriers, all of which are well-known in the art. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracistemally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agarxe2x80x94agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agarxe2x80x94agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 2,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depended on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.
The compounds of the present invention can exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.
In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The compounds of the present invention can be synthesized using standard organic methodology, including combinatorial chemistry or by biological processes such as through metabolism. It is intended that the present invention include compound made by any process.
The examples presented below are intended to illustrate particular embodiments of the invention, and are not intended to limit the scope of the specification or the claims in any way.